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临床研究
应用T1与T2加权比探讨阿尔茨海默病患者脑白质纤维髓鞘的改变
朱琳琳 王苗苗 李贤军 王小玗 刘聪聪 葛瑶 卞益同 高玲 杨健

Cite this article as: ZHU L L, WANG M M, LI X J, et al. Application of T1 and T2 weighted ratio to evaluate white matter fibers myelination changes in Alzheimer's disease[J]. Chin J Magn Reson Imaging, 2023, 14(3): 36-41.本文引用格式:朱琳琳, 王苗苗, 李贤军, 等. 应用T1与T2加权比探讨阿尔茨海默病患者脑白质纤维髓鞘的改变[J]. 磁共振成像, 2023, 14(3): 36-41. DOI:10.12015/issn.1674-8034.2023.03.007.


[摘要] 目的 应用T1与T2加权比探讨阿尔茨海默病(Alzheimer's disease, AD)患者脑白质纤维髓鞘的改变。材料和方法 基于常规T1加权和T2加权图像通过外部校准计算得到T1与T2加权比值图,并提取20条白质纤维束的T1与T2加权比值,比较26名AD患者与34名健康对照(healthy control, HC)者的脑白质纤维髓鞘差异,应用简易智能状态检查(Mini-Mental State Examination, MMSE)评估受试者的智力及认知功能的受损程度。采用两独立样本t检验和Mann-Whitney U检验比较AD组与HC组白质纤维束的T1与T2加权比值的差异;并将AD患者白质纤维束的T1与T2加权比值与MMSE评分进行Spearman相关性分析。结果 AD患者双侧皮质脊髓束(corticospinal tract, CST)、双侧扣带束(扣带部)[cingulum (cingulate gyrus), CgC]、右侧下额枕束(inferior fronto-occipital fasciculus, IFOF)、右侧下纵束(inferior longitudinal fasciculus, ILF)和双侧上纵束(superior longitudinal fasciculus, SLF)的T1与T2加权比值明显低于HC组(P<0.05);AD患者脑白质纤维束T1与T2加权比值与MMSE评分无显著相关性(P>0.05)。结论 T1与T2加权比作为一种临床可行的简单、快速且无创的髓鞘评估方法,为AD患者脑白质纤维髓鞘改变提供了有前景的评估指标,同时也为AD患者脑白质研究提供了新思路。
[Abstract] Objective To explore the changes of white matter fibers myelination of Alzheimer's disease (AD) with T1 and T2 weighted ratio.Materials and Methods Based on conventional T1WI and T2WI images, the T1 and T2 weighted ratio mapping was calculated by external calibration methods. The mean T1 and T2 weighted ratio of 20 white matter fiber tracts were extracted. The changes of white matter fibers myelination of 26 patients with AD and 34 healthy control (HC) subjects were compared. The Mini-Mental State Examination (MMSE) was used to evaluate the impairment of intelligence and cognitive function. Two independent samples t-test and Mann-Whitney U test were used to compare the T1 and T2 weighted ratio of white matter fiber tracts between the AD and HC group. Spearman correlation analysis was performed between the T1 and T2 weighted ratio and MMSE scores in AD patients.Results Compared with HC group, the T1 and T2 weighted ratio in AD group showed significant differences in corticospinal tract (CST), cingulum (cingulate gyrus) (CgC), superior longitudinal fasciculus (SLF), right inferior fronto-occipital fasciculus (IFOF), right inferior longitudinal fasciculus (ILF) (P<0.05). There was no significant correlation between the T1 and T2 weighted ratio and MMSE score in AD patients (P>0.05).Conclusions The T1 and T2 weighted ratio is a clinically feasible, simple, rapid and non-invasive myelin imaging method. It is a promising candidate index to evaluate the changes of white matter fibers myelination of AD patients, and provides a new idea for the study of the white matter of AD patients.
[关键词] 阿尔茨海默病;脑白质;髓鞘;磁共振成像;T1与T2加权比
[Keywords] Alzheimer's disease;white matter;myelination;magnetic resonance imaging;T1 and T2 weighted ratio

朱琳琳 1   王苗苗 1   李贤军 1   王小玗 1   刘聪聪 1   葛瑶 1   卞益同 1   高玲 2   杨健 1*  

1 西安交通大学第一附属医院医学影像科,西安 710061

2 西安交通大学第一附属医院神经内科,西安 710061

通信作者:杨健,E-mail:yj1118@mail.xjtu.edu.cn

作者贡献声明:朱琳琳撰写论文,参与数据采集、分析与解释和统计分析;杨健、王苗苗参与选题和设计,对论文内容的重要方面进行了关键修改;李贤军、王小玗、刘聪聪、葛瑶参与试验实施并对论文学术内容的重要方面进行了关键修改和指导;卞益同、高玲参与数据采集并对论文学术内容的重要方面进行了关键修改和指导;杨健获得了国家自然科学基金资助;全体作者都同意发表最后的修改稿,同意对本研究的所有方面负责,确保本研究的准确性和诚信。


基金项目: 国家自然科学基金 81971581
收稿日期:2022-10-24
接受日期:2023-03-03
中图分类号:R445.2  R749.16 
文献标识码:A
DOI: 10.12015/issn.1674-8034.2023.03.007
本文引用格式:朱琳琳, 王苗苗, 李贤军, 等. 应用T1与T2加权比探讨阿尔茨海默病患者脑白质纤维髓鞘的改变[J]. 磁共振成像, 2023, 14(3): 36-41. DOI:10.12015/issn.1674-8034.2023.03.007.

0 前言

       髓磷脂是中枢神经系统的核心组成部分,髓磷脂含量的减少和其结构的改变已被提出作为与年龄相关的认知能力下降的神经解剖学底物[1]。因此,有效评估大脑髓鞘含量具有重要意义。T1与T2加权比是一种评估大脑髓鞘含量的测量方法[2],在临床应用中具有较高的适宜性。该方法基于常规T1WI和T2WI图像,利用脑白质在T1WI上呈高信号、在T2WI上呈低信号的特点,提高了髓鞘信号的对比度和敏感性[3]。此外T1WI和T2WI信号强度不受纤维走行方向的影响,与其他评估髓鞘的方式如扩散张量成像(diffusion tensor imaging, DTI)、扩散峰度成像、磁化转移成像相比,在不增加扫描时间的同时具有较高的可靠性和理论基础[4, 5]。该方法最初被提出用于检测大脑皮层髓鞘的含量[3],随后扩展至包括白质在内的整个大脑[4,6, 7, 8],近些年已较多应用于发育和疾病的研究中。阿尔茨海默病(Alzheimer's disease, AD)是一种神经退行性疾病,占全球痴呆症的60%~80%,典型的病理改变为β-淀粉样蛋白(β-amyloid, Aβ)形成的神经炎性斑块和磷酸化tau蛋白高度螺旋化形成的神经原纤维缠结(neurofibrillary tangles, NFT)[9]。既往研究指出,白质异常特别是髓鞘和少突胶质细胞受损会加速认知障碍和AD病理学改变[9],其中NFT的相关毒性会导致脱髓鞘改变,而白质髓鞘的改变可能是AD进展过程中最早的特征之一[10],因此,探究AD患者脑白质髓鞘的改变具有重要意义。本研究应用T1与T2加权比探究AD患者脑白质纤维髓鞘的改变。

1 材料与方法

1.1 研究对象

       本研究经西安交通大学第一附属医院伦理委员会批准,免除受试者知情同意,批准文号:XJTU1AF2015LSL-066。回顾性分析2013年7月至2018年10月于西安交通大学第一附属医院确诊为AD的患者病例(AD组),纳入标准:(1)符合美国国立神经病、语言障碍和卒中研究所-阿尔茨海默病及相关协会(National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association, NINCDS-ADRDA)的诊断标准;(2)完整的MRI检查数据,包括T1WI与T2WI;(3)简易智能状态检查(Mini-Mental State Examination, MMSE)量表评分≤24分。排除标准:其他神经精神疾病或癫痫病、脑肿瘤或脑外伤史。收集年龄、性别与AD组匹配的同期健康对照(healthy control, HC)者(HC组)。纳入标准:(1)无明显认知功能障碍;(2)MMSE≥26分;(3)完整的MRI检查数据,包括T1WI与T2WI;(4)MRI检查脑白质Fazekas评分2分以下。排除其他神经精神疾病或癫痫病。

1.2 扫描设备及参数

       采用GE Signa HDxt 3.0 T、GE Discovery 750 3.0 T MR扫描仪行头颅扫描,扫描仪器及参数见表1

表1  MRI扫描仪器及参数
Tab. 1  MRI sequence parameters

1.3 图像后处理

       本研究采用GANZETTI等[6]提出的外部校准方法计算T1与T2加权比值图。具体流程如下:在SPM 12软件(Wellcome Trust Centre for Neuroimaging, London, UK)中将T2WI图像与T1WI图像配准,配准后的T2WI图像与T1WI图像进行偏倚校正和强度标准化,随后计算标准化后的T1WI图像与T2WI图像的比值,最终生成校准后的T1与T2加权比值图(图1)。为验证外部校准的有效性,使用SPM 12软件分割获得T1WI图像的白质概率图进行定量分析。

       为了便于进行组间比较,首先建立组内健康成人脑模板,将校准后的比值图从个体空间仿射到这一模板空间,再将约翰霍普金斯大学的白质纤维束图谱(JHU white-matter tractography atlas)仿射至该模板空间,最终提取20条白质纤维束的T1与T2加权比值,包括双侧丘脑前辐射(anterior thalamic radiation,ATR)、双侧皮质脊髓束(corticospinal tract, CST)、双侧扣带束(扣带部)[cingulum(cingulate gyrus), CgC]、双侧扣带束(海马部)[cingulum (hippocampus gyrus), CgH]、胼胝体压部(forceps major, Fma)、胼胝体膝部(forceps minor, Fmi)、双侧下额枕束(inferior fronto-occipital fasciculus, IFOF)、双侧下纵束(inferior longitudinal fasciculus, ILF)、双侧上纵束(superior longitudinal fasciculus, SLF)、双侧钩束(uncinate fasciculus, UF)、双侧上纵束颞部[superior longitudinal fasciculus(temporal part), tSLF]。

图1  T1与T2加权比值图处理流程图。
Fig. 1  T1 and T2 weighted ratio mapping processing workflow.

1.4 认知量表评估

       所有受试者采用MMSE量表评估认知能力,具体包括定向力、记忆力、注意力及计算力、回忆能力及语言能力,从而全面、准确、迅速地反映受试者智力状态及认知功能受损的程度。

1.5 统计学分析

       应用SPSS 20.0软件(IBM SPSS, Chicago, USA)进行统计学分析。采用Mann-Whitney U检验和卡方检验进行AD组与HC组的人口学资料比较,符合正态分布的计量资料以均数±标准差(x¯±s)表示,非正态分布的计量资料采用中位数±四分位数间距(M±Q)表示。两独立样本t检验和Mann-Whitney U检验用于比较校准前后两种扫描仪全脑白质T1与T2加权比值的组间差异以及AD组与HC组白质纤维束T1与T2加权比值的组间差异;AD患者白质纤维束的T1与T2加权比值与MMSE评分的相关性采用Spearman相关分析,P<0.05为差异有统计学意义。

2 结果

2.1 入组资料

       最终AD组入组26例,HC组入组34例。AD组与HC组的年龄、性别及其他临床指标组间未见明显差异(P>0.05),MMSE评分组间差异显著(Z=-5.70,P<0.001),结果见表2

表2  两组间人口学资料比较
Tab. 2  Comparison of demographic data between the two groups

2.2 校准前后不同扫描仪T1与T2加权比值的差异比较

       分别计算HC组校准前后的T1与T2比值图,并对全脑白质进行定量分析。结果显示:校准前两种仪器的T1与T2加权比值差异显著(Z=-4.24,P<0.05);而校准后两种仪器的T1与T2加权比值显示出较好的一致性,全脑白质的T1与T2加权比值在校准后组间无明显差异(t=-1.98,P>0.05,图2)。

图2  校准前后,经GE Signa HDxt 3.0 T、GE Discovery 750 3.0 T两种扫描仪扫描的全脑白质平均T1与T2加权比值分布箱式图。校准前两种扫描仪的全脑白质平均T1与T2加权比值存在组间差异(Z=-4.24,P<0.05)。校准后两种扫描仪的全脑白质平均T1与T2加权比值组间无显著差异(t=-1.98,P>0.05)。*表示P<0.05,校准前采用Mann-Whitney U检验,校准后采用两独立样本t检验。
Fig. 2  Before and after calibration, box plots of mean T1 and T2 weighted ratio distribution of whole brain white matter obtained from GE Signa HDxt 3.0 T and GE Discovery 750 3.0 T scanners. Before calibration, there is a significant difference in the mean T1 and T2 weighted ratio of whole brain white matter between the two scanners (Z=-4.24, P<0.05). After calibration, there is no significant difference in the mean T1 and T2 weighted ratio of whole brain white matter between the two scanners (t=-1.98, P>0.05). * represents P<0.05, Mann-Whitney U test is used before calibration, and the two independent sample t test is used after calibration.

2.3 基于白质纤维束的定量分析

       AD组双侧CST、双侧CgC、右侧IFOF、右侧ILF及双侧SLF的T1与T2加权比值显著低于HC组(P<0.05,图34)。

图3  AD组与HC组20条白质纤维束T1与T2加权比值组间差异结果。*表示P<0.05,**表示P<0.01,#表示采用Mann-Whitney U检验,其余采用两独立样本t检验。AD:阿尔茨海默病;HC:健康对照;L:左;R:右;ATR:丘脑前辐射;CST:皮质脊髓束;CgC:扣带束(扣带部);CgH:扣带束(海马部);Fma:胼胝体压部;Fmi:胼胝体膝部;IFOF:下额枕束;ILF:下纵束;SLF:上纵束;UF:钩束;tSLF:上纵束颞部。
Fig. 3  Differences in T1 and T2 weighted ratio of 20 white matter fiber tracts between AD and HC groups. * represents P<0.05, ** represents P<0.01, # represents Mann-Whitney U test, and the rest used two independent sample t test. AD: Alzheimer's disease; HC: healthy control; L: left; R: right; ATR: anterior thalamic radiation; CST: corticospinal tract; CgC: cingulum (cingulate gyrus); CgH: cingulum (hippocampus gyrus); Fma: forceps major; Fmi: forceps minor; IFOF: inferior fronto-occipital fasciculus; ILF: inferior longitudinal fasciculus; SLF: superior longitudinal fasciculus; UF: uncinate fasciculus; tSLF: superior longitudinal fasciculus (temporal part).
图4  AD组与HC组T1与T2加权比值有差异的白质纤维束。AD:阿尔茨海默病;HC:健康对照;L:左;R:右;SLF:上纵束;CgC:扣带束(扣带部);CST:皮质脊髓束;ILF:下纵束;IFOF:下额枕束。
Fig. 4  White matter fiber tracts with different T1 and T2 weighted ratio between AD and HC groups. AD: Alzheimer's disease; HC: healthy control; L: left; R: right; SLF: superior longitudinal fasciculus; CgC: cingulum (cingulate gyrus); CST: corticospinal tract; ILF: inferior longitudinal fasciculus; IFOF: inferior fronto-occipital fasciculus.

2.4 AD组T1与T2加权比值与MMSE评分相关性分析

       AD组患者20条白质纤维束T1与T2加权比值与MMSE评分之间无显著相关性(P均>0.05),如表3所示。

表3  AD患者白质纤维束T1与T2加权比值与MMSE评分的相关性
Tab. 3  Correlation between T1 and T2 weighted ratio of white matter fiber tracts and MMSE scores in AD patients

3 讨论

       本研究首次采用T1与T2加权比评估了AD患者脑白质纤维髓鞘的改变,结果显示AD患者双侧CST、双侧CgC、右侧IFOF、右侧ILF和双侧SLF等白质纤维束T1与T2加权比值较对照组显著降低,提示AD患者存在脑白质脱髓鞘。这一发现表明,T1与T2加权比在检测AD患者脑白质纤维髓鞘变化方面具有较高的敏感性。

3.1 外部校准流程的必要性

       T1与T2加权比被认为是反映髓鞘密度的标志,可以作为评估髓磷脂的间接指标,既往研究已经证明髓鞘图的变化(T1与T2加权比值)与皮质区域的细胞结构之间的一致性[3]。髓鞘水分数(myelinwater fration, MWF)因与髓磷脂组织学之间存在很强的相关性,被认为是髓磷脂的生物标志物。相关研究表明T1与T2加权比与髓鞘水分数具有低至中等程度的相关性,也说明T1与T2加权比在一定程度上对髓磷脂敏感且具有较高的重测信度[4,11],该方法目前已应用于评估多发性硬化症患者[2,12, 13]、AD患者[14]、自闭症患者[15, 16]大脑微观结构的损伤、新生儿脑白质髓鞘含量[7]以及青春期大脑皮层髓鞘发育[17]等疾病与发育方面的研究。然而不同的扫描仪、扫描参数会导致T1WI和T2WI图像组间强度尺度不一,GANZETTI等[6]提出的外部校准方法通过对图像进行偏倚校正和强度标准化,生成具有高重现性和低被试间差异的定量图谱,该方法可以提高不同数据集T1与T2加权比值的可重复性。本研究中纳入的数据来自两种扫描仪和扫描参数,为确保不同数据集的可比性,采用了该外部校准方法对数据进行了预处理,也发现校准后的T1与T2加权比值在不同扫描仪间无显著差异,进一步验证了外部校准的有效性。因此,应用T1与T2加权比值比较不同受试者、不同数据集的髓鞘含量之前,进行外部校准这一预处理流程是必要的,以保证数据的可比性以及结果的可靠性。

3.2 AD患者基于T1与T2加权比的白质纤维髓鞘的改变

       白质纤维束的髓鞘化是大脑发育和认知功能提升的基础[18]。本研究发现AD患者双侧SLF、右侧ILF的T1与T2加权比值减低,提示AD患者SLF、ILF中存在脱髓鞘现象,与本研究结果相符,既往研究发现AD患者双侧SLF连接区域白质MWF减低[19],神经突密度指数降低[20],YANG等[21]也发现AD患者SLF、ILF各向异性分数(fractional anisotropy, FA)值减低。先前的研究表明,载脂蛋白E基因(apolipoprotein E gene, APOE)ε4等位基因是AD的危险因素,APOEε4携带者SLF等白质纤维中的T1与T2加权比值显著降低,证实了白质纤维束在该高危人群中脆弱性的增加[22]。结合本研究结果,提示这种脱髓鞘改变可能在AD早期阶段就已经存在并持续发展,这种白质特性的改变可能与髓鞘丢失和少突胶质细胞受损有关,也与AD患者大脑白质存在髓鞘丢失的组织学结果相印证[9]。左额顶网络一般被认为是语言网络,SLF连接其外侧前额叶皮层和后顶叶皮层区域,相关研究发现,与认知相关的白质纤维束中断与AD患者的功能连接减少密切相关,且AD患者存在额叶网络连接性的下降[21,23, 24]。以上结果提示,SLF的脱髓鞘可能是AD患者额顶网络连接性下降,导致AD患者语言功能障碍的潜在因素。此外,有研究[25, 26]发现AD患者脑白质以与髓鞘发育相反的模式退化,即较晚髓鞘发育的纤维束(如SLF、ILF)更容易受到损伤,我们的结果在一定程度上验证了这种退化模式。

       CgC是扣带回与其他灰质结构的联络纤维,也是情节记忆环路重要的组成部分[27],IFOF与情绪、物体识别、认知功能和视觉处理有关,两条纤维束均在默认模式网络(default mode network, DMN)的相互连接中发挥作用[21]。以往研究表明DMN与AD患者中Aβ沉积分布部位之间的重叠[28],且髓鞘改变与Aβ病理学之间存在关联[29]。YASUNO等[30]发现早期Aβ诱导的病理变化可以通过T1与T2加权比值来检测。相关研究也发现AD患者的CgC、IFOF存在MWF、FA值减低,平均扩散率(mean diffusivity, MD)增加[19,31, 32]。我们的研究显示CgC、IFOF存在T1与T2加权比值的减低,这与上述研究结果相符,提示可能是AD患者Aβ沉积的相关病理改变导致CgC、IFOF的脱髓鞘改变,进而影响轴突传导以及DMN的连接性间接或直接导致AD患者的认知记忆功能障碍。

       CST起源于初级躯体感觉皮层和运动前区,连接感觉运动网络(sensorimotor network, SMN)[33],主要控制骨骼肌的随意运动。本研究发现AD患者CST存在T1与T2加权比值减低,与既往遗忘性轻度认知障碍阶段CST存在FA值减低、MD值增加[34, 35]的结果相符,提示AD患者或可能在更早期阶段就存在白质纤维束脱髓鞘现象。白质结构变化会导致网络功能的变化[36],YANG等[21]和BRIER等[28]发现AD患者也存在SMN连接性的降低,本研究结果发现AD患者CST的T1与T2加权比值减低,以上提示CST的脱髓鞘改变可能是导致SMN功能连接性下降,运动系统功能受累的潜在因素,我们的研究有助于阐明AD患者白质纤维髓鞘含量的改变,为AD患者中脑网络的改变提供了额外的证据。

3.3 T1与T2加权比值与MMSE评分的相关性

       MMSE评分对AD患者严重程度的评价有重要意义,既往研究发现,AD患者白质微观结构指标与MMSE评分存在相关性[37, 38],这与本研究的结果不相符。可能是由于本研究纳入的样本量较少,降低了统计效率;AD患者发病时间较短[病程为(21.50±11.51)个月,中位发病时间为22个月],尚未达到严重的临床认知功能障碍和全脑病理改变的阶段;其次,除脱髓鞘外,其他病理变化如铁沉积、炎症改变[39, 40]也可能影响T1与T2加权比值的大小,以上可能是导致本研究中T1与T2加权比值与MMSE评分的相关性不显著的原因。

3.4 本研究的局限性

       本研究尚存在以下不足:(1)样本量较少,后续仍需进一步扩大样本量进行纵向研究;(2)本研究采用基于图谱的感兴趣区分析方法得到白质纤维束的平均T1与T2加权比值,后续将进行基于体素的T1与T2加权比的分析,探索全脑范围内存在差异的区域;(3)本研究纳入的数据为常规序列图像,未行DTI扫描,除脱髓鞘外,其他改变(铁沉积、游离水或纤维密度)也可能影响T1与T2加权比值,下一步可将该技术与其他成像方法如神经突方向散度和密度成像相结合,以提高结果特异性和敏感性。

4 结论

       综上所述,基于T1与T2加权比这一方法提示了AD患者脑白质纤维的脱髓鞘改变,该方法可以作为评估AD患者脑白质纤维髓鞘变化的有前景的候选指标,为AD患者脑白质的研究提供了新思路。

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